Modular Instrumentation for Analyzing Biological Fluids

ABSTRACT

A modular analytic system includes a base, at least one fluid sample processing module configured to be removably attached to the base, at least one fluid sample analysis module configured to be removably attached to the base, a fluid actuation module positioned on the base, a fluidic network comprising multiple fluidic channels, in which the fluid actuation module is arranged to control transport of a fluid sample between the at least one sample processing module and the at least one sample analysis module through the fluidic network, and an electronic processor, in which the electronic processor is configured to control operation of the fluid actuation module and receive measurement data from the at least one fluid sample analysis module.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.16/265,635, filed on Feb. 1, 2019, which is a continuation of U.S.application Ser. No. 15/101,061, filed on Jun. 2, 2016, which is a 371application of International Application No. PCT/US2014/068941, filed onDec. 5, 2014, which claims the benefit of U.S. Provisional ApplicationNo. 62/064,846, filed on Oct. 16, 2014, and U.S. Provisional ApplicationNo. 61/912,224, filed on Dec. 5, 2013. The contents of each of theseapplications is incorporated herein by reference in its entirety.

STATEMENT OF FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with Government support under U54GM062119 andP41EB002503, awarded by the National Institutes of Health. TheGovernment has certain rights in the invention.

BACKGROUND

This disclosure relates to systems for analyzing biological fluids. Inparticular, this disclosure relates to an analytic system in which oneor more components of the system are modular in nature and connectableto a fluidic network via standardized connectors.

As biological diagnostics have increased in complexity over the pastdecades, there has been a trend for diagnostics and testing equipment tobe removed from points of care, such as a physician's office, and movedto centralized laboratory service locations. At least in part, thistrend was due to perceived problems in quality control stemming fromperforming testing at various points of care with traditional diagnostictechnology. For example, in comparison to a large medical center with asizable staff of highly skilled technicians, a small town physician'soffice with a small independent lab was believed to lack the oversightand technical support necessary to properly operate and servicecomplicated laboratory equipment.

Such trends have been reinforced by federal legislation and regulations,such as those imposed by the Clinical Laboratory Improvement Act (CLIA)of 1988, despite protests from physicians' organizations. From 1988forward, many physician office laboratories were closed, as they wereunable to comply with the requirements of the CLIA. As of 2011, morethan 90% of all diagnostics testing was performed in centralizedlaboratories.

While this centralized approach may have been a solution for controllingthe quality of diagnostic information considering the technology at thetime, it is not without its problems. Perhaps the greatest problem isthat patients in medically underserved areas, which are primarily servedby physicians operating out of small or mobile offices, now had reducedaccess to important diagnostic testing. Test samples either needed to becollected and transported (which can present potential additional costand handling) or patients needed to travel to a centralized laboratoryfacility to have tests performed (which may require that patients livingin rural environments travel a great distance, which can dissuade somepatients from having the test performed at all due to the cost or thetime associated with travel).

Very recently, some attempts have been made to move more diagnostictesting back to or towards the point of care. However, their limitedadoption reveals the many challenges of moving testing to the point ofcare in the current healthcare environment. Among the problems are thatmost current point of care solutions either significantly sacrificequality to try to compete with centralized laboratory services on cost(for example, most lab-on-a-chip designs have a target price point thatrequires significant tradeoffs between cost and performance) or are notparticularly economical as a whole (for example, multiple systems arerequired for various types of analytes and many physicians must stillrely a centralized laboratory to meet at least some of their routinetesting needs).

Still further, most point of care laboratories have separate systems fordifferent diagnostic tests. At a small or medium sized testing facility,it can be hard to justify the expense of separate systems for differenttypes of tests where testing volume is relatively low. Further,selecting a suite of efficient devices is often difficult as there isoften redundant, unshared hardware across the various devices yet, dueto differences in the device interfaces, middleware must still beobtained to integrate and connect the various devices into a singlelaboratory information system. At the same time, having multiple testingdevices takes up significant laboratory real estate and can meanseparate systems to operate and maintain, separate contracts to manage,and separate manufacturers and vendors. Thus, even with the highdesirability of a return to point of care diagnostics testing, currentlythere has been very limited adoption of this model.

Hence, a need exists for improved administration of diagnostic testing.Among other things, there is a strong need for improved distribution andservicing of reliable diagnostics equipment at mid- and small-sizedpoints of care.

SUMMARY OF THE INVENTION

The present disclosure relates to improved systems and methods fordiagnostics testing. The new systems enable sophisticated and complextesting equipment to be implemented at the point of care and enable anefficient and distributed diagnostics infrastructure. By designing theanalytic system to have modular components, which may be of aplug-and-play type, systems can be built that are both flexible in thetypes of diagnostic tests that they can perform and that are easilyserviceable and/or upgradeable by the replacement of one or more of themodules. Replacement modules can be shipped or couriered to the point ofcare and modules that need to be repaired or serviced can be sent to askilled technician who resides off-site. In some embodiments, one ormore of the modules may be non-serviceable or disposable.

Among other things, the disclosed systems potentially permit thehealthcare landscape to shift more types of testing and care back to thepoint of care for primary care delivery, where the testing and caremight be more efficiently administered by physicians, physicians'assistants, and nurse practitioners. Even a modest shift of testing backto mid-tier laboratories, in which highly specialized labor is notrequired to be on-site to maintain and service diagnostics equipment,would reduce access barriers to healthcare and improve service quality.A modular analytic system of the type disclosed herein accommodates theshift to this distributed health care model by permitting more of thediagnostics testing to occur closer to or at the point of care.

Furthermore, the modular analytic systems described herein are readilyemployable in research laboratories, where the flexibility of the device(due to its modular nature) permits the laboratory to build its owndevice ala carte to include only the diagnostics modules of interest.Further, because the modular systems can accommodate plug-and-play typemodules, the analytic systems can be readily rebuilt or expanded as theneeds of the laboratory change. Additionally, the integration of samplecapture, handling, measurement, and diagnostics in a single system thatis reconfigurable depending on the desired tests to be performed canenable significant reductions in costs relative to systems that employone or more of those features using separate platforms.

In general, in one aspect, the subject matter of the present disclosurecan be embodied in a modular analytic system (or systems) that includesa base, at least one fluid sample processing module configured to beremovably attached to the base, at least one fluid sample analysismodule configured to be removably attached to the base, a fluidactuation module positioned on the base, a fluidic network includingmultiple fluidic channels, in which the fluid actuation module isarranged to control transport of a fluid sample between the at least onesample processing module and the at least one sample analysis modulethrough the fluidic network, and an electronic processor, in which theelectronic processor is configured to control operation of the fluidactuation module and receive measurement data from the at least onefluid sample analysis module.

Implementations of the system can include one or more of the followingfeatures. For example, in some implementations, the system furtherincludes a cartridge, in which the cartridge includes: one or more firstreceptacles configured to store a fluid sample; one or more secondreceptacles configured to store a reagent; and one or more thirdreceptacles. The fluid sample processing module can include an openingto receive the cartridge. The sample processing module further caninclude an actuation input port and a fluid output port, in which theactuation input port and the fluid output port are arranged to couple tothe third receptacle of the cartridge when the cartridge is positionedin the opening of the sample processing module. The base can include afirst connector interface coupled to the fluid actuation module, inwhich the actuation input port of the sample processing module isconfigured to mate with the first connector interface. The board caninclude a fluidic connector interface coupled to the fluidic network, inwhich the fluidic output port of the sample processing module isconfigured to mate with the fluidic connector interface.

In some implementations, the at least one fluid sample analysis moduleincludes a light detector module, an electrochemistry module, acytometry module, or a Coulter counter module.

In some implementations, the at least one fluid sample analysis moduleincludes multiple internal tubes, in which at least one tube is arrangedto receive a fluid sample from the fluidic network and at least oneother tube is arranged to deliver a fluid sample to the fluidic networkwhen the at least one fluid sample analysis module is attached to thebase.

In some implementations, the system includes multiple the fluid sampleanalysis modules removably attached to the base, in which at least onefluid sample analysis module is arranged to deliver a fluid samplethrough the fluidic network to at least one other fluid sample analysismodule.

In some implementations, the fluid actuation module includes a pneumaticpump or a hydraulic pump to supply pneumatic pressure or hydraulicpressure, respectively, to the fluidic network. The fluid actuationmodule can include a manifold that separates the pneumatic pressure orthe hydraulic pressure supplied by the fluid actuation module intomultiple independent channels. The fluid actuation module can includemultiple valves, in which the electronic processor is operable tocontrol the operation of the plurality of valves.

In some implementations, the fluid actuation module is removablyattached to the base. The fluid actuation module can include one or moreprotrusions or openings, in which, for each protrusion or opening on thefluid actuation module, the base includes a corresponding opening orprotrusion that frictionally fits to the protrusion or opening.

In some implementations, the system further includes a waste moduleconfigured to be removably attached to the base, in which the wastemodule includes a fluidic connector interface that mates with one ormore of the fluidic channels. The waste module can include one or moreprotrusions or openings, in which, for each protrusion or opening on thewaste module, the base includes a corresponding opening or protrusionthat frictionally fits to the protrusion or opening. The fluidicactuation module can be operable to control the flow of fluid samplesfrom the at least one analytic module to the waste module.

In some implementations, the fluidic channels are formed in the base.

In some implementations, the fluidic channels include multiple tubes.

In some implementations, at least one seal is between the fluidicnetwork and the at least one fluid sample analysis module. The at leastone seal can include a sealing gasket interposed between the at leastone fluid sample analysis module and the fluidic network. The at leastone fluid sample analysis module can include an internal tube, and theat least one seal comprises an O-ring that forms a sealed pathwaybetween the internal tube and a corresponding fluidic channel of thefluidic network. The at least one fluid sample analysis module caninclude an internal tube, in which the at least one seal includes asealing gasket interposed between the fluidic network and an exteriorsurface of the at least one fluid sample analysis module, and in whichthe internal tube extends, at least in part, through an opening in thesealing gasket to form a sealed pathway between the internal tube and acorresponding fluidic channel of the fluidic network. Compression of thesealing gasket between the fluid network and the exterior surface of theat least one fluid sample analysis module can cause the opening of thesealing gasket to compress around the internal tube.

In some implementations, each of one or more modules selected from thegroup consisting of the fluid sample processing modules and the fluidsample analysis modules includes a surface having at least oneprotrusion, and the base includes, for each protrusion, a correspondingopening that mates with the protrusion.

In some implementations, each of one or more modules selected from thegroup consisting of the fluid sample processing modules and the fluidsample analysis modules includes a surface having at least one opening,and the base includes, for each opening, a corresponding protrusion thatmates with the opening.

In general, in another aspect, the subject matter of the disclosure canbe embodied in methods that include: providing a base including a fluidsample processing module, a fluid sample analysis module, and a fluidactuation module, in which each of the fluid sample analysis module andthe fluid sample processing module is removably attached to the base,and in which the fluid sample processing module and the fluid sampleanalysis module are coupled together through a fluidic channel networksupported by the base; providing a fluid sample to the fluid sampleprocessing module; activating the fluid actuation module so that thefluid sample is transferred from the fluid sample processing modulethrough the fluidic channel network to the fluid sample analysis module;performing an analysis of the fluid sample in the fluid sample analysismodule to obtain measurement data; and transmitting the measurement datato an electronic processor.

Implementations of the methods can include one or more of the followingfeatures. For example, in some implementations, providing the fluidsample to the fluid sample processing module includes providing thefluid sample to a cartridge including a receptacle configured to store afluid sample, and receiving the cartridge in an opening in the fluidsample processing module. The cartridge can include a reagent, and themethods can further include mixing the fluid sample with the reagent toprovide a pre-processed fluid sample. An input port of the fluid sampleprocessing module can be coupled to the fluid actuation module through aconnector interface on the base, in which an output port of the fluidsample processing module is coupled to the fluidic channel network.Activating the fluid actuation module can include supplying pneumatic orhydraulic pressure to the input port such that the pre-processed fluidsample is transported from the output port to the fluidic channelnetwork. The methods can further include incubating the fluid samplewith the reagent and/or separating the fluid sample into a plurality ofaliquots.

In some implementations, activating the fluid actuation module includesoperating one or more valves on a manifold to provide pneumatic pressureor hydraulic pressure to the fluid sample processing module.

In some implementations, the methods further include activating thefluid actuation module to transport the fluid sample from the fluidsample analysis module to a waste container supported by the base. Thewaste container can be removably attached to the base.

In some implementations, performing an analysis of the fluid sample inthe fluid sample analysis module includes performing cytometry on thefluid sample, detecting a response to the application of anelectromagnetic field or current to the fluid sample, performing anelectrochemical reaction with the fluid sample, or imaging the fluidsample.

According to one aspect of the disclosure, a modular analytic systemincludes one or more sample preparation systems, one or more modulardetectors, and a fluidic network (which may, in some forms, include orbe a fluidic motherboard such as base 150 in FIG. 2). The fluidicnetwork includes one or more sets of connectors for selective connectionof the fluidic network to the sample preparation system(s) and one ormore sets of connectors for selective connection of the fluidic networkto the modular detector(s). The fluidic network places the samplepreparation system(s) in fluid communication with the modulardetector(s).

The modular analytic systems are flexible in their application. Forexample, the modular analytic systems can have a sample preparationsystem that is cartridge-based for point-of-care testing diagnostics ina clinical environment. Such a system may have the modular analyticsystem perform as an integrated bench-top clinical analyzer forperforming panels of assays including hematology, clinical chemistry,urinalysis, immunoassays, and/or combinations thereof. As still anotherexample, the sample preparation system can include a well plate andpipetting arrangement and the modular analytic system can permit an enduser to develop their own assays such as may be more common in aresearch environment.

In some implementations, the modular analytic system includes a flowcontrol subsystem that is integrated with the fluidic network to controlthe flow of fluids between the sample preparation system and the modulardetector(s). The flow control subsystem can further control the flow offluids from a mixing module to one of the modular detectors. The flowcontrol subsystem can control the flow of fluids, e.g., using one ormore of a pneumatic pump and a hydraulic pump.

One of the advantages of the modular approach described herein is thateach of the modular detectors can be fully integrated and include all ofthe components necessary to perform one or more assays. One or more ofthe modular detectors can be adapted to process a multitude ofindependently run assays simultaneously. For example, these multipleassays can be performed in a multiplexed or parallel fashion. In stillother forms of the device, multiple assays can be performed in series ormultiple samples can be processed in series. As one specific example,one or more of the modular detectors can include a multiplexedphotometry system. As another specific example, one or more of themodular detectors include a multi-parametric flow cytometer.

Another advantage of the modular approach described herein is that themodular analytic system is customizable and the fluidic network can beadapted to support various combinations of modular detectors. Theconnections between the fluid network and the modular detector(s) can beof a plug-and-play type connection in which the connection between themodular detector(s) and the fluid network provides the modulardetector(s) with all of the fluidic inputs and outputs for an operationof the modular detector(s). By making the modular detectors easilyreplaceable, a module that requires service can be removed and a workingmodule inserted in its place. By permitting such easy replacement of amodule, a non-working module can be quickly replaced with a workingmodule and the non-working module can be serviced at the convenience ofa skilled technician or may be disposable. In contrast, many “hardwired”non-modular testing devices require a technician to come on-site torepair or service the device. This can lead to long operationaldowntimes in which the equipment is non-functional and cannot beutilized.

The modular analytic systems can further include a controller thatcommunicates with and/or controls one or more of the modular detectorsand/or the flow control subsystem. In some forms, the modulardetector(s) include an electrical connection for communication with thecontroller.

With respect to the connectors, the set(s) of connectors for connectingthe fluidic network to the modular detector(s) may include a pluralityof tubes that place channels in the fluidic network and the modulardetector(s) in fluid communication with one another. Seals can be formedbetween the plurality of tubes and one or more of the fluidic networkand modular detector(s). The seal(s) include a sealing gasket interposedbetween the fluidic network and a coupling manifold or member in whichthe plurality of tubes extend, at least in part, through openings in thesealing gasket. The compression of the sealing gasket between the fluidnetwork and the coupling manifold or member can cause openings of thesealing gasket to compress around the plurality of tubes to assist informing the seal(s).

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods, materials,and devices similar or equivalent to those described herein can be usedin the practice or testing of the present invention, suitable methods,materials and devices are described below. All publications, patentapplications, patents, and other references mentioned herein areincorporated by reference in their entirety. In case of conflict, thepresent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and notintended to be limiting.

The details of one or more embodiments are set forth in the accompanyingdrawings and the description below. Other features, objects, and will beapparent from the description, drawings, and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

It should be understood that the drawings are provided for the purposeof illustration only and are not intended to define the limits of theinvention. The present invention is not limited to the precisearrangements and instrumentalities shown in the drawings, and thedrawings are not necessarily to scale, emphasis instead being placedupon illustrating the principles disclosed herein.

FIG. 1 is a schematic that illustrates an example of a modular analyticsystem as disclosed herein.

FIG. 2 is a schematic that illustrates an overview of differentcomponents of a modular analytic system.

FIG. 3 is a schematic that illustrates an example of a general processcovered by a modular analytic system.

FIG. 4 is a schematic illustrating the operational connectivity of anexample of a modular analytic system.

FIG. 5 is a high-level schematic overview that illustrates how a numberof components can be arranged to create different examples of modularanalytic systems according to various aspects described herein. Thisfigure shows alternative configurations for the fluidic network ormotherboards, lists a number of analytic modules that may be selectivelyconnected to the network, some options for sample preparation modules,and some examples of combined analytic systems constructed from thesecomponents.

FIG. 6A is a top view of a fluidic network with various modulardetectors and a mixing module attached thereto.

FIG. 6B is a top side perspective view of the fluidic network withvarious modular detectors and the mixing module attached thereto fromFIG. 6A (albeit with the housing or covers from some of the modulesremoved to reveal the interior parts).

FIG. 6C is a top side partially exploded perspective view of theassembly shown in FIG. 6B revealing some of the various components inthe various modules.

FIG. 6D illustrates the fluidic network and modules of FIG. 6B in whicha sample preparation system is schematically illustrated as beingconnected to the network to provide sample(s) and/or reagent(s).

FIGS. 7A-7E are schematics that illustrate various views of a modularanalytic system.

FIGS. 7F-7G are schematics that illustrate two different possiblefluidic connection configurations to a fluidic motherboard.

FIG. 8 is a three-dimensional schematic that illustrates an example of asample preparation system in the form of a sample handler.

FIG. 9A illustrates an example of an integrated cytometer module (ICM).

FIG. 9B illustrates an example of an integrated photometry module (IPM).

FIG. 9C is an exploded view of the integrated photometry module in FIG.9B.

FIGS. 10A-10B are schematics that illustrate an example of an analyticalmodule that fits into a module seat of a fluidic motherboard.

FIG. 11 is an exploded view of the portion of a connection assemblyincluding a housing, tubes, tube holder, and custom gasket.

FIG. 12A is a top side partially exploded view of a module separatedfrom the fluidic network to illustrate a gasket disposed therebetween.

FIG. 12B is a perspective view of a bottom side of a module toillustrate a gasket disposed thereon.

FIG. 13 is a bottom side partially exploded view of the module separatedfrom the network (in an assembly similar to that shown in FIG. 12A) toillustrate the gasket therebetween.

FIG. 14 is a cross-sectional side view taken through a seal area betweenthe module and the network to show how the tubes and gasket place thenetwork and the module in fluid communication with one another.

FIG. 15A is a schematic illustrating a cross-section of a technique forforming fluidic seals in an analytical module

FIG. 15B is a schematic illustrating an O-ring for making axial andradial seals in an analytical module.

FIG. 15C is a schematic that illustrates a cross section view of amodule that utilizes both the gasket seal and O-ring seal.

FIG. 15D is a schematic that illustrates a cross-section view of agasket seal.

FIG. 16 is an exploded perspective view of the mixing system moduledetached from the fluidic network.

FIG. 17A is a schematic illustration of the pneumatic control system.

FIG. 17B is a schematic illustrating a perspective view of the entirepneumatic module.

FIG. 18A is a schematic illustration of the electronic control system ofa modular analytic system.

FIG. 18B is a block diagram illustrating an overview of the differentlevels of data acquisition, processing and analysis that may beperformed by one or more analytical modules.

FIG. 19 is a schematic illustrating the sample processing that may beperformed using the modular analytic system.

FIGS. 20 through 22 are high-level schematics that show variousembodiments of the valving for a hydraulic or pneumatic control system.

DETAILED DESCRIPTION

FIG. 1 shows an example of a modular analytic system 100. Asillustrated, the modular analytic system 100 includes a central unit 102which houses a fluidic network and various modular components as will bedescribed in greater detail below.

The modular analytic system 100 is adapted to receive a number of inputsand outputs. On a front face of the central unit 102 of the modularanalytic system 100, there may be a slot 104 or other type of receivingarea for the selective introduction of a sample preparation unit such asthe assay cartridge 106. The assay cartridge 106 may receive, contain,and store one or more samples and may receive, contain, and store one ormore reagents for performing assays of the sample(s). Sample(s) mayinclude, for example, any one of a number of types of biological fluidsincluding, but not limited to blood, urine, saliva, and so forth. Thesamples and/or reagents include one or more samples and/or reagents ofthe same or different types. For example, multiple blood samples couldbe supported on a single sample preparation system and these samplescould be either from the same or from different patients. As anotherexample, different types of samples could be provided on a singlecartridge (for example, blood and urine from the same patient). Unlessspecified in the claims, nothing in this application should be soconstrued as limiting the type, number, and combinations of samples andreagents that may be carried by the sample preparation system.

Although a cartridge-based system is illustrated in FIG. 1, it should beappreciated that other types of sample preparation systems may be used.Some of these alternative sample preparation systems will be describedbelow. For example, the sample preparation system could incorporate apipetting/well plate configuration for a more research-orientedenvironment. Of course, the slot 104 or means for connecting the samplepreparation system to the central unit 102 of the modular analyticsystem 100 may be modified or adapted to accommodate a connectionbetween whatever sample preparation system is used and the internalfluidic network and modules.

The central unit 102 may include either or both of wired connections(such as enabled by cable 108) and wireless connections (such as enabledby a wireless adapter, illustrated by wireless signal lines). For easeof use and connection, there may be a single cable 108 that connects thecentral unit 102 to a controller or computer and may be adapted toprovide both a data connection and a power connection. Similarly,separate data and power connections may be supplied. However, it is alsocontemplated that there may be multiple cables for power, data, and orboth.

In the form illustrated in FIG. 1, there is also a separate and optionalauxiliary unit 110 that is attached to the central unit 102. In the formillustrated, the auxiliary unit 110 is adapted to perform moleculardiagnostics and lateral flow assays and is in communication with thecentral unit 102.

FIG. 2 is a schematic that illustrates an overview of the differentcomponents of the modular analytic system 100 in more detail. As shownin FIG. 2, the system includes a support base 150 (also called a fluidicmotherboard) that acts as a support for holding and securing togetherthe different modular components in a single compact system. In someimplementations, the base 150 also includes at least a portion of thefluidic network. The fluidic network includes multiple fluidic channelsthrough which fluid can be transported between the different modularunits of the modular analytic system 100. The fluidic channels can beformed within the base 150 and have openings and/or seals that fluidlycouple to the different modular components. In some implementations,some or all of the fluidic channels are formed external to the base 150.For instance, in some cases, the fluidic channels include tubing that iscoupled to the different modular components of the analytic system. Thefluidic channels can be fluidly coupled and sealed to the differentmodular components using custom gaskets, as will be described below. Insome implementations, the fluidic channels of the fluidic network arereconfigurable. That is, the particular connections that the fluidicchannels make with the sample processing modules and the analyticalmodules may be rearranged according to different predefinedconfigurations, such that a user can modify the modular analyticalsystem for desired operations.

The base 150 can be composed of, for example, glass or plastic. In someimplementations, the base 150 also includes the electrical connectionsfor power and data communication. For instance, in some cases, the base150 includes a printed circuit board (PCB) designed to have one or morelayers of electrical connections using any standard PCB computer aideddesign software and fabrication techniques (e.g., mask and chemicaletching techniques). In certain implementations, the base 150 may be asubstantially contiguous elongated board or frame.

The modular analytic system 100 also includes one or more sampleprocessing modules 152, also called sample preparation modules. Eachsample processing module 152 receives, contains, and stores one or moresamples and may receive, contain, and store one or more reagents forperforming assays of the sample(s). The sample processing module 152 canbe in the form of a cartridge, chip, or any appropriate casing that iscapable of receiving and storing the sample(s). Alternatively, thesample processing module can be a casing that is capable of receiving aseparate cartridge (e.g., cartridge 106, which is received in slot 104of FIG. 1) that, in turn, receives, contains, and stores one or morefluid samples and that may receive, contain, and store one or morereagents for performing assays of the sample(s). In the case the sampleprocessing module 152 is capable of receiving a cartridge that storesthe sample fluid/reagent, the sample processing module 152 can includeconnections that allow access to the fluid sample in the cartridge aswell as connections that allow an actuation source to couple to thecartridge. Although the opening in the sample processing module forreceiving the cartridge 106 is shown as a slot 104 in FIG. 1, theopening may be an appropriate aperture or space that is capable ofreceiving the cartridge.

In the example shown in FIG. 2, the sample processing module 152includes separate receptacles 153 internal to the module, each of whichis configured for a different use, such as storing the sample, storingthe reagent, and storing/forwarding the sample after it has reacted withthe reagent. Again, the receptacles 153 can be part of a separatecartridge that is received by the sample processing module 152. Forinstance, the cartridge can include a well plate with wells for storingthe fluid sample, reagent, and forwarding the fluid sample and/or amixture of the fluid sample and reagent. The sample processing module152 can include internal fluidic channels (e.g., internal tubes) thatconnect the different receptacles so that the sample and reagent can becombined within the module 152 and transported from the module 152 tothe fluidic network. In some implementations, the internal fluidicchannels are formed as part of the sample processing module 152 andconnect to a cartridge containing the receptacles when the cartridge isreceived by the sample processing module 152. The sample processingmodule 152 prepares the fluid sample to be tested (e.g., by combiningthe fluid sample with a reagent) and stores it in the store/forwardreceptacle until it is ready to be transferred from module 152 forfurther processing. The sample processing module 152 or a cartridge thatis received by the sample processing module 152 can include multiplefluid sample receptacles, reagent receptacles, and store-forwardreceptacles, e.g., if the module 152 is used to perform multiple testson the fluid sample.

The sample processing module 152 also is configured to securely mount tothe base 150 while also being detachable from the base 150 for disposal,cleaning and re-use or to replace with another sample processing module.The sample processing modules can fluidly connect to one or more fluidicchannels of the fluidic network through sealing areas formed on the base150. Further details of the sample processing module and cartridges thatmay be received by the sample processing module can be found in U.S.Provisional Application 62/064,846, filed on Oct. 16, 2014, the subjectmatter of which is incorporated herein by reference in its entirety.

To transport the fluid samples (e.g., from the sample processingmodules, through the fluidic network, to the analytical modules, and/orto waste channels), the modular analytic system 100 also can include afluid actuation power source module 154. Similar to the preprocessingmodule 152, the fluid actuation power source module 154 can beconfigured to securely mount to the base 150 while also being detachablefrom the base 150. The fluid actuation power source module 154 can betemporarily coupled to the store/forward internal receptacle(s) of oneor more of the sample processing module(s) 152 through standardizedinterface(s). For instance, the sample processing module(s) 152 caninclude an interface that includes one or more input actuation portscoupled to the store/forward receptacles, such that when the interfaceis coupled to the fluid actuation power source module 154, the pneumaticor hydraulic pressure output by the module 154 is delivered to thestore/forward receptacle(s) of the sample processing module 152.

The fluid actuation power supply module 154 can be a device, such as apneumatic or hydraulic pump, that provides a source of actuation (e.g.,compressed gas) to force the fluid samples to move through the fluidicchannels.

In the example shown in FIG. 2, the fluid actuation power supply module154, when activated, applies pneumatic pressure through an actuationinput port 149 of the store/forward receptacle, causing any sampleand/or reagent contained within the receptacle to move from the sampleprocessing module 152 to a fluidic channel through a fluidic output port151 of the store/forward receptacle. The input port 149 and output port151 can be part of standardized connector interfaces on the sampleprocessing module 152. In some implementations, the input port 149 andoutput port 151 are fluidly coupled to the store/forward receptacle whenthe store/forward receptacle is a part of a cartridge received by thefluid sample processing module.

In some implementations, the modular analytic system 100 includes asingle fluid actuation power source having an output (e.g., pneumatic orhydraulic) that is split into multiple different independent channels(e.g., one for each sample processing module) through a manifold. Inother implementations, the modular analytic system 100 includes multipleindependent fluid actuation power supplies, each of which is coupled toa separate sample processing module.

The modular analytical system 100 also includes one or more analyticalmodules 156. Similar to the sample preprocessing modules 152, theanalytical module(s) 156 are supported by the base 150 and areconfigured to securely mount to the base 150 while also being detachablefrom the base 150 for cleaning and re-use or to replace with anotheranalytical processing module. In some cases, the analytical module(s)156 may be disposable. The analytical module(s) 156 can be in the formof a cartridge, chip, or any appropriate casing that is capable ofreceiving and storing the sample(s). The analytical module(s) 156include components that are configured to analyze the fluids transportedfrom the sample processing module(s). For instance, the analyticalmodule(s) 156 can include hardware components such as sensors,electronic processors, and memory, among other electronic components,for performing measurements of fluids, for generating and processingmeasurement data resulting from the measurements, and for transmittingthe signals to a central processing unit for further analysis.

In the example shown in FIG. 2, the analytical module 156 includes asignal source 157 (e.g., a light source such as a light emitting diodeor laser, a voltage source, an electric current source, or other signalsource) configured to generate a signal for interacting with the fluid,a detector 159 configured and arranged to detect the signal after thesignal has interacted with the fluid and to generate measurement data,and module electronics 161 configured and arranged to receive themeasurement data and perform pre-processing on the measurement data(e.g., perform noise reduction on the measurement data, amplify themeasurement data, or perform other signal conditioning). The analyticalmodule 156 also can include a measurement receptacle 163 for holding thefluid received from a sample processing module or from anotheranalytical module. The measurement receptacle 163 can include an inputport 165 for receiving a fluid from a fluidic channel through a seal onthe base 150 or from tubing coupled to the base 150. The measurementreceptacle 163 also can include a fluid output port 167 for coupling toanother fluidic channel so that the fluid can be transferred from theanalytical module 156 after measurement (e.g., to a waste chamber or toanother analytical module). Further details on fluid sample analyticalmodules can be found in PCT Patent Application Publication No.WO2014078785, filed Nov. 18, 2013 and entitled “SYSTEM AND METHOD FORINTEGRATED MULTIPLEXED PHOTOMETRY MODULE,” and PCT Application No.PCT/US2014/062426, filed on Oct. 27, 2014 and entitled “MODULARINSTRUMENTATION FOR ANALYZING BIOLOGICAL FLUIDS.” The subject matter ofeach of those applications is incorporated herein by reference in itsentirety.

The modular analytical system 100 also can include a central processingunit (CPU) 158 that is supported by the base 150. The CPU 158 can beelectronically coupled to one or more of the different modularcomponents of the system 100 through wiring and electronic interfacesformed in or on the base 150. The CPU 158 includes an electronicprocessor and may have other hardware components (e.g., memory,switches, or other active and passive electrical components) forgenerating control signals and for receiving and analyzing measurementsignals from the analytical modules. The CPU 158 also can include acommunication port for electronically receiving external input signals(e.g., from another computer) and for transmitting output signals (e.g.,measurement data) to a display or other computer.

The modular analytical system 100 also can include a waste container(not shown in FIG. 2) that is supported by the base 150 and isconfigured to securely mount to the base 150 while also being detachablefrom the base 150 for cleaning and re-use or for being replaced withanother waste container. The waste container is coupled to the fluidicchannels downstream from the one or more analytical modules 156 andcollects waste fluids that have passed through the analytical modulesafter analysis.

FIG. 3 is a schematic that illustrates an example of a general processcovered by the modular analytic system 100. First, a fluid sample (e.g.,a biological fluid sample such as blood) is received in a samplepreparation module (such as module 152 in FIG. 2), where the fluidsample may be stored, separated into aliquots, mixed, and/or incubatedwith a reagent. For performing the sample preparation actions (e.g.,mixing, incubation, separation), the CPU can send control signals to thesample preparation module to instruct the module to perform the desiredactions. The fluid sample may be manually loaded into the samplepreparation module using, for example, pipetting. When loading the fluidsample, the module can be positioned on and attached to the base 150 orlocated separate from the base 150. If separate, the sample preparationmodule can be attached to the base 150 after loading such that thefluidic output(s) from the module fluidly couple to one or more fluidicchannels of the fluidic network.

After loading the fluid sample and performing any applicable samplepreparation (e.g., obtaining aliquots, mixing and incubation), the fluidactuation power supply (e.g., pneumatic power supply 154) may beactivated to transport the prepared fluid sample from the preparationmodule (e.g., from the store/forward receptacle) through the attachedfluidic channels to the appropriate analytical module, where theprepared fluid sample is analyzed. In some implementations, certainsample preparation steps, such as mixing and incubation are performed ona second separate sample preparation module that receives the fluidsample from the first sample preparation module. After performing theanalysis, the pneumatic supply may again be activated to transport thefluid sample from the analytical module to the waste container throughthe fluidic channels. The activation of the fluid actuation powersupply, sample preparation modules, and analytical modules can becontrolled by the CPU.

FIG. 4 is a block diagram illustrating a schematic setup of the modularanalytic system and the interaction of the various components. In thesystem, a blood sample (which could be another type of sample or samplesas noted herein) is introduced into a sample preparation module (e.g., acartridge) that may also be used to store one or more reagents. Thiscartridge can be placed in communication with the fluid network andmodules after the sample or samples are processed. The processed samplesmay be provided to a mixing/incubation module on a fluidic network boardbefore being transported to one or more analytic modules which are alsodisposed on the fluidic network and are in communication with themixing/incubation module. As explained above, to transport the fluidsample between the various stages and modules, a pneumatic controlsystem and/or a hydraulic control system may be used. If, for example, apneumatic control system is used, then this system may receivecompressed gas from a compressed gas supply and regulator. The variousstages and modules may be connected to electronics such as a controllerfor controlling and communicating with the various modules and forrouting various signals. In some instances, these electronics may be incommunication with a computer that includes software and a graphicaluser interface (GUI) for controlling operation of the system.

Now with additional reference to FIG. 5, some of the various componentsthat could be used to construct the modular analytic system areillustrated, as well as systems that could be constructed using thesecomponents.

In the first column of FIG. 5, two different configurations of fluidicnetworks or motherboards are illustrated: Configuration A andConfiguration B. In both instances, there are various sets of connectorson the fluidic networks (indicated by the internal rectangles) that maybe adapted for configuration to either a sample preparationsystem/module or an analytic module. It is noted that the twoillustrated networks are only illustrative and are not the only twoconfigurations that the fluidic networks may have.

In the second column of FIG. 5, various analytical modules areillustrated that may be selectively connected to the fluidic networks.These include (1) a photometry module, (2) an electrochemistry module,(3) a mix and incubate module, (4) a cytometry module, (5) a Coultermodule, and (6) an imaging module. The illustrated analytic modules donot constitute the only modules that can be used and are onlyrepresentative of some of the envisioned modules. For the purposes ofdistinguishing the modules from one another in the illustration, theyare each given a different size and/or shape and, in the fourthanalytical system column, are provided with numbers that correlate totheir identification in the second column. It is contemplated thatdifferent types of modules do not necessarily need to have a differentsize and shape and, in some instances, may actually have similar sizesand shapes so that connectors (described in greater detail below) may bestandardized to match the matching or corresponding connectors on thefluidic network for attachment. However, it is also contemplated thatthe shapes and sizes might intentionally be made different to help anend user distinguish between the various modules and/or to help indicateto the user that a particular module is connectable to a particular setof connectors on the fluidic network.

In the third column, two examples of sample preparation modules orsystems are illustrated including a cartridge preparation module and awell plate preparation module. A cartridge preparation module may bemore appropriate for the use in a clinical environment, whereas a wellplate preparation module may be more appropriate for use in a researchenvironment. Again, types of sample preparation modules may be usedother than those illustrated and it is contemplated that the systemcould also receive one or more sample preparation modules at the sametime (even in a single analytic system) or be adapted to receive morethan one type of sample preparation module.

In the fourth column, some exemplary analytic systems are illustratedthat have been constructed using the components from the first threecolumns. As a first example, a cartridge clinical point of care testingsystem is illustrated as being buildable from configuration A of thefluidic network, three photometry modules, three cytometry modules, amix and incubate module, and a cartridge preparation module. As a secondexample, a well plate biological research system is buildable fromconfiguration A of the network, an electrochemistry module, twophotometry modules, three cytometry modules, a mix and incubate module,and a well plate preparation module. As a third example, a well platehigh throughput (HT) cytometer is built using configuration B of thenetwork, six cytometry modules, a mix and incubate module, and a wellplate preparation module. Again, these three examples are forillustrative purposes only, and it is contemplated that various othertypes of analytical systems could be built using the modular componentsthat are disclosed or other modules and/or fluidic networkconfigurations.

FIGS. 6A through 6D illustrate an example of an assembly 200 of afluidic network 202 and various modules, outside of any case or housingin which the system may be received. This particular assembly 200includes the fluidic network 202 that is similar to the configuration Anetwork illustrated in FIG. 5. This network 202 has a mix and incubatemodule 204, three photometry modules 206, 208, and 210, and threecytometry modules 212, 214, and 216 attached thereto. It should be notedthat these various modules 204-216 may be selectively connected to thefluid network 202 in a plug-and-play type manner such that the modules204-216 may be readily added or removed from the network 202 to promoteeasy construction and maintenance of the system 200.

The plug-and-play type connections may be between the modules 204-216and the network 202 and include an intermediate connection assemblyincluding tubes, gaskets and so forth as will be described in greaterdetail below. Further, in the form illustrated, the plug-and-playconnections are primarily fluidic in nature (i.e., placing the variouschannels in the modules in fluid communication with channels or openingsformed in the fluidic network). Separate electrical or data connectionsare available on the outside of the modules for connection to acontroller or controllers for transmitting (i.e., sending or receiving)data or signals from the modules and/or providing power to the modules.In the form illustrated, these electrical connectors are shown on thelateral sides of some of the modules 204-216 (e.g., see the connectorson the front side of the modules 206-210 in FIG. 6B). However, it iscontemplated that attachment of the modules to the network could alsoinclude connections of an electrical type to permit transmission ofelectrical data, signal, or power, for example in addition to thesefluidic connections.

The fluidic network 202 also includes a set of connectors 218 forconnection to a sample preparation system 220 or module. With referenceto FIG. 6D, the assembly of FIGS. 6A through 6C is shown with the samplepreparation system 220 or module attached to the network 202 at this setof connectors 218 which is adapted to place the fluidic channels of thefluid network 202 in fluid communication with channels or reservoirs ina sample preparation system 220, when the sample preparation system 220is attached. The attachment of the sample preparation system 220 to thenetwork is abstractly illustrated in FIG. 6D. The sample preparationsystem 220 is attached to provide one or more test samples (e.g., blood,urine, etc.) and/or one or more reagents to the fluidic network 202 viathe set of connectors 218. The fluid can be drawn out of the samplepreparation system 220 or module using a hydraulic or pneumatic moduleattached to the network 202 and in communication with the fluidicchannels in the network 202 or can be transported into the fluidicsystem using some transport mechanism that is integrated with the samplepreparation system 220 or module.

The sample preparation system 220 or module can take a number of forms.It is contemplated that it could be a cartridge (as may be common in aclinical environment), a pipetting/well plate configuration (as may becommon in a research environment), or some other type of samplepreparation system.

FIGS. 7A-7D illustrate an alternate example of a modular analytic system250. As shown in FIG. 7A, the system 250 includes a base/fluidicmotherboard 252 that supports multiple detachable modules 254 and adetachable pneumatic power source 256. The detachable modules 254include one or more sample processing modules and one or more analyticalmodules. For instance, the detachable modules 254 can include modulesfor mixing and/or incubating fluid samples with reagents, modules forperforming assays, modules for performing photometry, and/or modules forperforming cytometry, among other types of modules. As noted, thepneumatic power source 256 serves as the power source for actuatingfluids amongst the various sample handling modules. The board 252 alsosupports the fluidic network for routing the prepared sample from thedetachable modules to one or more other detachable modules or to a wastecontainer. Referring to FIG. 7E, the board 252 also can include adetachable sample preparation module 258. When the sample preparationmodule 258 is attached to the board 252, channels or wells containedwithin the module 258 fluidly couple to a fluidic interface 260 (seeFIG. 7A). In addition, the module 258 also is coupled to the pneumaticpower supply through a pneumatic interface 262 (see FIG. 7A).

When the sample preparation module 258 is attached, the module 258 isable to provide one or more test samples (e.g., blood, urine, etc.)and/or one or more reagents to the fluidic network through the fluidicinterface 260. The fluid can be drawn out of the sample preparationmodule 258 using the pneumatic power supply 256 that is in communicationwith the module 258 through the pneumatic interface 262. FIG. 7B is aschematic that shows a perspective view of the modular analytic system250 with the modules 254 and pneumatic power supply 256 detached fromthe board 252. FIG. 7C is a schematic that illustrates a reverse side ofthe board 252. As shown in FIG. 7C, the board 252 also supportsprocessing electronics 264, including a CPU. The processing electronics264 can be coupled to the various modules through electrical connectionsto permit transmission of electrical data signals, control signals,and/or power signals. The board 252 also supports a detachable wastecontainer 266. The waste container is coupled to the fluidic channelsdownstream from the one or more modules 254 and collects waste fluidsthat have passed through the analytical modules after analysis.Additionally, the board 252 can include a manifold 268 (e.g., apneumatic manifold). The manifold 268 is coupled to the pneumatic powersupply 256 and enables the air pressure provided by the power supply 256to be divided into multiple separate pneumatic channels, where eachpneumatic channel can then be used to actuate fluid samples fromdifferent modules. FIG. 7D is a schematic illustrating an exploded viewof the reverse side of the board 252, and showing the module electronicinterfaces 270 (for coupling electronic signals to and from theprocessing electronics 264), the backside of the module fluidicinterfaces 272 for fluidly coupling the fluidic channels to the modules,and the backside of the fluidic transport channels 274.

The fluidic connections that couple the pneumatic power supply, themodules and the waste container can have various configurations. FIGS.7F and 7G are schematics that illustrate two different possible fluidicconnection configurations to a fluidic motherboard. In bothconfigurations, the fluidic motherboard contains a fluidic manifold thatdelivers prepared sample from the sample processing module through oneof multiple access ports.

The configuration shown in FIG. 7F is referred to herein as “completelyvariable.” In this configuration, the fluidic motherboard 252 contains aset of module seats (three example footprints are shown) that canaccommodate a module of a particular sized footprint. Within each moduleseat, there is a large access hole 278 in the fluidic motherboard 252through which the module can be fluidly connected to the fluidicmanifold 276 that contains multiple fluidic access holes 278. Thisconnection can be made by fluidic channels that interface with thefluidic access holes 278 and the module. The fluidic channels can be inthe form of tubes for carrying the fluid samples. The ends of the tubescan be coupled together in a coupler or “fluidic header,” that attachesto the manifold or the module. Thus, for a particular module, onefluidic header connects to the fluidic manifold and the other connectsdirectly to the module itself. The tubes corresponding to the fluidicchannels can be held together in a tube ribbon/bundle or free standingtubes.

Through the large access hole 278 in the module seat, the module is alsoconnected electrically to the remainder of the analyzer electronics.With this configuration, modules can be replaced with the onlyconstraint being that they have to fit into one of the availablefootprints. The number and location of fluidic and electricalconnections to each module are completely variable and so, the systemcan be reconfigured such that any module can access any port in thefluidic manifold.

The configuration shown in FIG. 7G is referred to as “Semi Variable.” Inthis configuration, the fluidic motherboard 252 contains a set of moduleseats that have pre-defined fluidic access holes 280 and electricalconnection sites 282. In this case, the ports in the fluidic manifoldare “hardwired” to particular fluidic access hole locations on thefluidic motherboard or to a particular module seat. For instance, theports can be coupled to the access holes or modules seats throughdefined fluidic channels formed within the board itself. Alternatively,the fluidic channels can include tubes arranged in a ribbon/bundle orfree standing tubes. For the modules to properly attach to the board252, the modules must have a spatial footprint that conforms to the seatdimensions and each module's fluidic and electrical connections must belocated at pre-determined locations corresponding to the access holes280 and electrical connection sites 282 when the modules are positionedon the board 252. Although not shown, the fluidic mother board in eitherthe completely variable or the semi variable configuration can includeopenings (e.g., grooves) or protrusions that are configured to mate withprotrusions or openings, respectively, on the modules, so that themodules may be removably attached to the board surface.

An example of a sample preparation system 300 is illustrated in FIG. 8.In this example, sample preparation system 300 includes a housing orframe with a lower half 302 and an upper half 304, which are fastenabletogether via side attachment latches 306. The lower half 302 and theupper half 304 are arranged between a sample tray 308 and anintermediate member 312. The sample tray 308 is receivable in the lowerhalf 302 (i.e., may be seated in the lower half 302) and includes anumber of wells 310 for receipt of samples, sample vials or containersfor holding samples, reagents, or vials or containers for holdingreagents. The intermediate member 312 is placed between the sample tray308 and the upper half 304 and includes a number of channels 314. Thesechannels 314 place the wells 310 (or the sample or reagent holdersreceived therein) in communication with channels or conduits formed inthe upper half 304 of the housing. The exposed connections 316 on thetop of the upper half 304 of the housing of the sample preparationsystem 300 may then be adapted for connection to a fluidic network ofthe modular analytic system (via the channels or conduits, for example).There are multiple channels for each well illustrated so as to create acircuit that accommodates circulation and pumping of fluids from thewells into the system and vise-versa.

The sample preparation system 300 illustrated in FIG. 8 is only oneexample of a sample preparation system and there may certainly bemechanical variations to this system or other types of samplepreparation systems utilized in the modular analytic system. Turning nowto FIGS. 9A-9C, examples of two analytical modules are shown apart anddetached from the fluidic network.

In FIG. 9A, an integrated cytometry module 400 is illustrated forperforming flow cytometry which includes the components to analyzeparticles in a biological sample. For example, a fluid sample processedby the integrated cytometry module 400 will identify particles orconstituents of a sample having a particular specified quality. Thevarious components of the integrated cytometry module 400 may include alaser and light and/or color detectors for transmitting light throughparticles or cells in the fluid sample being tested and for receivingthe forward scatter or emitted light from the florochromes of theparticles or cells, a means (typically a flow chamber) for ensuring thatthe particles or cells of the biological sample are aligned as they flowthrough the area between the laser and the light detector, any filtersappropriate to direct the emitted light to the appropriate colordetector, and the associated electronics used to operate the moduleand/or assist in detection or quantification, amplification, and so onof the detected light signals. While the specific details of thecomponents of the module 400 are not described in great detail, it isobserved that the module 400 is adapted for connection to a fluidicnetwork on its bottom side 402 (usually using tubes and one or moregaskets) so as to receive the fluid sample for testing. Further, thereis an electrical connector 404 on the front side of the module 400 thatmay receive a plug for connection to a controller or other computersystem that can provide a data connection as well as be used to supplypower to the module 400. The particular integrated cytometry module 400illustrated has two forward scatter, one side scatter, and onefluorescent channel for performing complete blood counts, cellularimmunophenotyping and immunoassays. In terms of size, the integratedcytometry module 400 can have a very small package size and in oneembodiment may be 6.5 inches by 2.5 inches by 3.5 inches.

In FIG. 9B, an integrated photometry module 500 is illustrated. Eachphotometry module 500 may contain 10 independent cuvettes giving theoverall system the capability of performing 15 chemical assays inparallel. The remaining 15 cuvettes may run a standard blank for qualitycontrol. The 10 channel multiplex photometer can have wavelengthsranging from 400-800 nanometers to cover the full spectrum of clinicalchemistry analytes. As with the ICM 400, the integrated photometrymodule 500 has a set of fluid connectors on its bottom side 502 and aset of electrical connectors 504 on its front side for data and/or powerconnection. In the illustrated form, the integrated photometry module500 may have dimensions of approximately 3.5 inches by 2.5 inches by 3inches.

Looking at FIG. 9C, the integrated photometry module 500 of FIG. 9B isexploded to show the various internal components of the module 500. Themodule includes a coupling manifold 506, an LED board 508, a plastichousing 510, aluminum heat sinks 512 and 514, a chip 516 with fluidchannels for the testing sample interposed between the heat sinks 512and 514, Peltier heaters 518, a resistance temperature detector (RTD)520, and a detector board 522. In operation, the fluid sample flowsthrough the chip 516 and light produced from the LED board 508 istransmitted through the fluid sample in the chip 516 (and apertures inthe heat sinks 512 and 514 surrounding the chip 516) and is detected bythe detector board 522.

Again, the modules 400 and 500 are illustrative of modules that may beconnected to the fluidic network in a plug-and-play type fashionaccording to one aspect of the invention. Of course, the types ofmodules should not be limited to either these types of modules nor tothe specific types or construction of the modules illustrated.

FIGS. 10A and 10B are schematics illustrating another example of adetachable analytical module that fits into a module seat of a fluidicmotherboard, such as the seats shown in FIG. 7G. FIG. 10A is aperspective view of the top surface of the module whereas FIG. 10B is aperspective view of the bottom surface of the module. As shown in FIG.10B, the surface fluidic seals 550 (e.g., gaskets or O-rings) andsurface electrical connections 552 are illustrated as well. The fluidicseals 550 and surface electrical connections 552 can be removablyattached to corresponding interface connectors formed on the fluidicmotherboard.

In addition, the detachable analytical module includes protrusions 554that fit securely into and mate with corresponding holes or openings inthe fluidic motherboard. The protrusions 554 can be posts, ridges,flanges, bumps or other mechanisms that allow the module to be properlypositioned and fixed in place on the fluidic motherboard. In someinstances, the friction created by the protrusions helps secure themodule to the board. This is also known as an interference fit,frictional fit, or press fit. Though protrusions are shown on the bottomsurface of the module in FIG. 10B, other mechanisms allowing the moduleto be detachably secured to the board also can be used. For example,instead of protrusions, the bottom surface of the module may containgrooves or other openings configured to receive and mate withcorresponding protrusions formed on the surface of the fluidicmotherboard, such that the protrusions and grooves form an interferencefit/frictional fit/press fit. Alternatively, the module and board mayinclude any suitable latching mechanism that can be secured to hold themodule in place on the board and unsecure to allow the module to beremoved from the board. In some implementations, the module is securedto the board solely through the electrical and fluidic connections.Modules other than the analytical modules (e.g., the sample processingmodules, the fluidic actuation modules, the waste container, and theCPU) also can include any of the foregoing mechanisms for detachablysecuring those modules to the fluidic motherboard.

Turing now to FIG. 11, a connection sub-assembly 600 is illustrated thatmay be used to establish fluidic communication between conduits andopenings or fluidic channels in the fluidic network. In some forms, thefluidic network may not have channels formed therein, but may havevarious conduits that connect elements or openings on the network to oneanother. Alternatively, the connection sub-assembly 600 may be used toestablish direct fluidic communication between conduits, openings, orfluidic channels formed in a fluid sample processing or analysis module.This sub-assembly 600 includes a housing 602 having a plurality ofopenings 604, a plurality of tubes 606, a tube holder 608, and a customgasket 610. The plurality of tubes 606 can be received in the tubeholder 608 and extend toward a lower side of the housing 602, and theends of these plurality of tubes 606 may be placed in fluidcommunication with external conduits. The bottom ends of the tubes 606will extend out of the bottom side of the tube holder 608 and intoopenings in the custom gasket 610. When the custom gasket 610 iscompressed between the tube holder 608 and a surface of the network ormore specifically a motherboard of the network, the custom gasket 610forms a seal between each of the plurality of tubes 606 and the network,and places the tubes 606 in fluid communication with openings orchannels in the network.

Turning now to FIGS. 12 through 14, the connection interface for one ofthe modules 206 shown in FIGS. 6A-6D with the network 202 isillustrated. The connection interface concept shown in FIGS. 12-14 canbe used with any of the fluid sample processing modules and the fluidsample analysis modules. In this instance, the customizable gasket 222and a gasket seat 224 on the underside of the module 206 are interposedbetween the surface of the network 222 and the underside of the module206. The plurality of tubes 226 from the module 206 extend through thegasket seat 224 and gasket 222 as is best illustrated in the assembledcross-sectional view of FIG. 14 to connect the fluidic channels 228 inthe network 202 to the fluid channel 232 in the integrated photometrychip in the module. As with the other connection sub-assembly 600 thatwas illustrated, when the module 206 is attached to the network 202, thegasket 222 compresses around the tubes 226 to form a seal between thetubes 226 and the network 202. The tubes 226 do not need to extend intothe openings or channels 228 formed in the network, although the tubes226 can extend for some distance into the module 206 in order to supplythe fluid at the channel 232 in the chip. Though FIGS. 12-14 show aconnection interface for a photometry module, the same concept may beapplied to other modules. For example, in some implementations, thesample processing module (see FIG. 2) can include a gasket arranged in agasket seat for sealing the actuation input port to a correspondingconnector interface on the fluidic mother board that is coupled to thefluid actuation device. Similarly, the sample processing module caninclude a gasket arranged in a gasket seat for sealing the fluid outputport to the fluidic channels 228 in the network 202.

As shown in FIG. 12B, the bottom surface of the module 206 includesmultiple protrusions 230 that allow the module 206 to be removablyattached to the fluidic motherboard. In the present example, theprotrusions 230 are configured to mate with corresponding openings(e.g., to allow the module to achieve an interference fit/frictionalfit/press fit with the fluidic motherboard). The connection illustratedis exemplary and not intended to be limiting.

FIG. 15A is a schematic illustrating a cross-section of anothertechnique for forming fluidic seals in an analytical module 1500. Inthis example, O-rings 1502 are used to make seals both axially andradially at the two ends of an internal tube 1504 that is used totransport a fluid sample from a fluid access hole in the fluidic motherboard to a region within the module where the analysis of the fluidsample is performed (i.e., fluidic chip 1506 in FIG. 15A). FIG. 15B is adetailed view of the axial and radial seals made by the O-ring 1502. Asshown in FIG. 15B, the O-ring 1502 has a defined outer diameter 1501 andis seated in a groove in the O-ring seat 1512 on the underside of themodule, in which the O-ring 1502/groove has a fixed depth 1503 in theseat 1512. A tube 1504 located internally within the module passesthrough the center of the O-ring causing the O-ring elastomer tocompress and form a radial seal. The O-ring 1502 also forms a faceseal/axial seal with the surface of the fluidic mother board when themodule is positioned on the board in the correct seat.

FIG. 15C is a schematic that illustrates a cross section view of amodule 1550 that utilizes both the gasket seal 1508 and O-ring seal1502. The gasket 1508 is used for creating an axial seal at theinterface with the fluidic motherboard and the O-rings 1502 are used tocreate axial seals between the internal tubing 1504 and the fluidic chip1506 within the module. FIG. 15D shows a detailed view of the gasketseal 1508. The gasket 1508 includes multiple sealing rings 1510 thatform the axial seal between the tubing and the fluidic motherboard. Thedepth and diameter of the sealing rings 1510 are important for creatingthe seal. Additionally, a thin membrane 1511 connects all of the sealingrings 1510 so that they form the single sheet gasket 1508.

FIG. 16 illustrates the internal components of a mix and incubate module700 (that may be similar or identical to the mix and incubate module204) including a housing and actuator 702, mixing channels 704, and flowsensors 706. This module can also include a heater in order to provideincubation of the samples being tested. The mix and incubate modulehelps to minimize cost per test and maximize assay menu flexibility byproviding a space for mixing and incubating assays with temperaturecontrol.

FIG. 17A illustrates a pneumatic control system routingboard/distribution network 1702. This board 1702 can be configured topneumatically transport the fluid samples through various individualassay lines or all of the lines at a system level by properconfiguration of the various switches. FIG. 17B is a schematicillustrating a perspective view of the entire pneumatic module 1700including examples of valves 1704, the pneumatic distribution network1702, the electronics control board 1706, and the module housing 1708.

With additional forward reference to FIGS. 20 to 22, the fluidconnectivity of a power source for transport (such as a pneumatic orhydraulic control system) is illustrated. In each of FIGS. 20 to 22,small rectangles are used to indicate valved items, although the largerrectangles are used to generally indicate and group the system level,the module level, and the intra-module level features.

Looking first at FIG. 20, it can be seen that the power source isconnected to various system level control features including a valve forproviding fluid (either liquid or gas) to perform a prime function and avalve for providing fluid to perform a rinse function. As indicated inthe figure annotation, the branched channel architecture indicates thatthe valved line connects to system wide channels (that is, to allanalytical elements). There is also a main flow valve at the systemlevel control that selectively connects the hydraulic or pneumatic powersource to the various module level controls. In the form illustrated,when the main flow valve is opened, it places the power source in fluidcommunication with the IPM1 valve, the IPM2 valve, and the ICM valve viarespective fluid lines. Each of the valves illustrated in FIG. 20 may beformed on the pneumatic manifold. Although valves for three modules areillustrated, it is contemplated that there could be valves to separatelyregulate flow to any number of modules. Each of the IPM1 valve, the IPM2valve, and the ICM valve may be independently operated to provide fluidand control fluid flow to the respective module. Still yet, when one ormore of the module level control valves are open, a fluid is supplied tothe respective module(s) and there may be additional valves within eachmodule that separately control flow to the intra-module components, suchas cuvettes 1, 2, and 3 in the IPM modules. However, it is contemplatedthat for some modules, such as the ICM, it may not be necessary to haveintra-module valving. The output flow at the far right end of theschematic may then be disposed of or redirected into the system,depending of the particular function being performed.

By control of these various valves at different levels (system, module,intra-module), the system may be selectively controlled to regulate theflow of fluid into the various parts of the fluidic network and theattached modules for testing of the fluid. Control of the various valvesmay be directed by software or testing or diagnostic programs, but theremay also be ways for a user to discretely control the valves formaintenance or by programming the device.

Turning now to FIG. 21, an alternative schematic is providedillustrating the hydraulic or pneumatic architecture of the fluidicnetwork. In this example, there are only valved controls available atthe system level (for example, prime, main flow, and rinse) and at themodule level (for example, IPM1, IPM2, and ICM). In the particularillustrated embodiment in FIG. 21, there is not discretely valvedcontrol of intra-module elements such as cuvettes as with the embodimentillustrated in FIG. 20. Thus, for example, if flow to IPM1 is turned on,all of the cuvettes in IPM1 receive this fluid flow.

Alternatively, the module level controls might be eliminated asillustrated in the embodiment of FIG. 22. In this embodiment, there aresystem level valved controls (prime, main flow, and rinse) andintra-module level valved controls or analytical element level controls(cuvettes 1, 2, and 3). In this arrangement, there are not intermediatemodule level valved controls for separately regulating flow into thevarious modules.

The systems illustrated in FIGS. 20 to 22 are intended to beillustrative of some hydraulic or pneumatic systems, but should not beconsidered as the only possible ways to control hydraulic or pneumaticflow of a fluid. Other variations, for example, the addition or removalof valving at different levels of the system, are contemplated.

Turning now to FIG. 18A, the setup of the electronic system for amodular analytic system is illustrated schematically. Various systemelements are illustrated in the boxes [e.g., the power supply, thepower/signal board or controller, the modules, the control modules forpneumatic control and mixing, the auxiliary systems such as lasers andpressure regulators, a computer, and data acquisition (DAQ) equipmentfor the modules and system control]. The sharing or electricalcommunication of signals or power is indicated by the arrows linking theboxes.

For example, power is supplied by the power supply to the power/signalboard. The power signal board supplies this power to the modules fordetection and analysis of the samples, the modules for pneumatic andmixing control, and the auxiliary systems. It is contemplated that theDAQ equipment and the computer may be separately powered.

In terms of system control, the computer passes digital commands andanalog voltages to the DAQ equipment which may be passed to thepower/signal board or central controller. The power/signal board canthen pass these digital commands and analog voltages to the detectormodules and the control modules to perform their appropriate operations.The detector modules can return pre-conditioned signals and raw signalsto the power/signal board and the control modules can pass raw signalsback to the power/signal board. The power/signal board can then sendpre-conditioned and raw signals to the DAQ for the detector modules andsend the raw signals from the control modules back to the DAQ for thesystem control elements. The DAQ devices can then send conditionedsignals back to the computer. In the setup illustrated, the computer andthe auxiliary systems are able to pass device specific command andresponses back and forth with one another.

It should be appreciated that the digital commands, analog voltages, rawsignals, pre-conditioned signals, and conditioned signals may be passedthrough some of the equipment (e.g., the DAQ equipment or thepower/signal board) or may be processed and appropriately convertedalong the way. Whether additional signal processing may occur willdepend on the capabilities and configuration of the various hardwareelements in the setup.

It is separately noted that in some instances the DAQ equipment might beintegrated with the power/signal board or provided as a card or the likethat can be installed in and implemented in the computer.

Thus, it will be readily appreciated that the system setup of FIG. 18Ais illustrative, but not intended to be limiting, as there arevariations that could be made to this setup by one having ordinary skillin the art without deviating from the modular aspects of the system ofthis disclosure.

As explained herein, each analytical module may perform various levelsof signal conditioning and analysis before measurement signals aretransmitted from the module to the control electronics for furtherprocessing and analysis. FIG. 18B is an overview of several differentlevels of data acquisition, processing and analysis that may beperformed by one or more analytical modules coupled to the fluidicmotherboard. The different levels of operations are denoted as “1,” “2,”and “3,” and may overlap. In a first example configuration, a moduleonly does basic analog signal processing (e.g., amplifying measurementsignals, current to voltage conversion, filtering, among other basicanalog signal processing) before passing the measurement signal to thecentral processing unit. In a second example configuration, the moduleadditionally performs digital signal processing (e.g., conversion of ananalog measurement signal to a digital measurement signal, addition orsubtraction of digital signals, digital filtering) before passing themeasurement signal to the central processing unit. In a third exampleconfiguration, the module also performs signal analysis that may benecessary to generate data that is useful for clinical evaluationpurposes (e.g., identification of signal peak values or identificationof temporal signal properties such as frequency or period). The outputin this case can be passed directly into the CPU for conversion to aclinical value in software before reporting (e.g., being output to adisplay or saved in memory).

Turning to FIG. 19, a sample processing schematic is provided forprocessing of a whole blood input according to one aspect of use of themodular system. This illustration shows how a single sample may be splitand routed a number of different ways to perform simultaneous testing ofthe same.

As illustrated, the whole blood input is provided from the sampleprocessing system into the modular analytic system. The whole bloodinput is split six ways into six different conduits. A first portion ofthe whole blood is mixed with a hemoglobin reagent in a 100:1 ratio and50 microliters is provided to one of the integrated photometry modulesfor processing. A second portion of the whole blood undergoes plasmaseparation and this then mixed in a 100:1 ratio with a glucose reagentbefore 50 microliters is provided to one of the integrated photometrymodules for processing. A third portion of the whole blood alsoundergoes plasma separation and is mixed with an alkaline phosphatase(ALP) reagent in a 13:3 ratio before providing 50 microliters of thesample to one of the integrated photometry modules for processing. Afourth portion of the whole blood is mixed with a first white blood cell(WBC) reagent in a 20:1 ratio and is mixed in a 5:2 ratio with a secondand a third WBC reagents that have been mixed in a 3:1 ratio; 80microliters of this sample is then delivered to the integrated cytometrymodule. A fifth portion of the whole blood is mixed in a 1000:1 ratiowith a red blood cell/platelet (RBC/PLT) reagent and 20 microliters issupplied to the integrated cytometry module. A sixth portion of thewhole blood is mixed with a basophil (BASO) reagent in at a 40:1 ratioand 80 microliters is supplied to the integrated cytometry module.

OTHER EMBODIMENTS

A number of embodiments have been described. Nevertheless, it will beunderstood that various modifications may be made without departing fromthe spirit and scope of the invention. Other embodiments are within thescope of the following claims.

1. A modular analytic system comprising: a base; at least one fluidsample processing module configured to be removably attached to thebase; at least one fluid sample analysis module configured to beremovably attached to the base; a fluid actuation module positioned onthe base; a fluidic network comprising a plurality of fluidic channels,wherein the fluid actuation module is arranged to control transport of afluid sample between the at least one sample processing module and theat least one sample analysis module through the fluidic network; and anelectronic processor, wherein the electronic processor is configured tocontrol operation of the fluid actuation module and receive measurementdata from the at least one fluid sample analysis module. 2.-25.(canceled)
 26. A method comprising: providing a base comprising a fluidsample processing module, a fluid sample analysis module, and a fluidactuation module, wherein each of the fluid sample analysis module andthe fluid sample processing module is removably attached to the base,and wherein the fluid sample processing module and the fluid sampleanalysis module are coupled together through a fluidic channel networksupported by the base; providing a fluid sample to the fluid sampleprocessing module; activating the fluid actuation module so that thefluid sample is transferred from the fluid sample processing modulethrough the fluidic channel network to the fluid sample analysis module;performing an analysis of the fluid sample in the fluid sample analysismodule to obtain measurement data; and transmitting the measurement datato an electronic processor. 27.-34. (canceled)